The long term aims of this project are 1) to determine whether 3,4 dihydroxy-pheylglycolaldehyde (DOPEGAL) is an endogenous neurotoxin; 2) to determine whether in Alzheimer's disease (AD) the concentration of DOPEGAL increases in epinephrine (Epi) nerve cell bodies where it has access to DNA and where binding to DNA could decrease transcription of the mRNAs of functionally important proteins. Four experiments are proposed: 1. The concentration of DOPEGAL and enzymes involved in its synthesis will be measured in Epi neuronal cell bodies in AD and controls using gas chromatography-mass spectrometry and radiochemical assays. 2. The mRNA levels of catecholamine synthesizing enzymes will be measured in Epi neuronal cell bodies in AD and controls using polymerase chain reaction (PCR) and quantitative autoradiography. 3. In vivo toxicity will be determined by injecting DOPEGAL onto norepinephrine neurons in the rat locus ceruleus. Histologic evidence of toxicity will be determined by counting neurons and measuring cross sectional areas of neurons identified immunohistochemically. Chemical evidence of toxicity will be determined by measuring activity and amounts of catecholamine (CA) synthesizing enzymes using radiochemical and immunochemical assays, CA enzyme mRNA levels will be measured using polymerase chain reaction with autoradiography and quantitative densitometry. 4. The precise identity of the neurotoxin and whether its effects are mediated by extracellular cell surface receptor mechanisms or by purely intracellular mechanisms of toxicity will be determined in vitro using cultured adrenal medullary explants. Evidence of toxicity will be determined using the above histological and chemical procedures. In addition, HPLC-EC measurements of the MAO-A metabolites will be made to determine their uptake into cells. CA uptake blockers will be used to determine if effects are mediated by intracellular mechanisms. Neuronal death is the anatomic basis for clinical symptoms in AD yet cellular and subcellular mechanisms underlying neuronal degeneration are poorly understood. The Epi neurotransmitter system is affected late in AD. While Epi neurons are undergoing degeneration there is no cell loss making it an ideal system to look at the biochemical mechanisms of neuronal degeneration.